The bromodomain and extra terminal (BET) proteins are key regulators of immune response genes, and their dysregulation is linked to various diseases including cancer. The extra terminal (ET) domain of BET proteins functions as a crucial interaction hub for transcription factors, chromatin regulators and viral proteins through linear peptide motifs, making them potential targets for peptide-therapeutic strategies. While BRD3 and BRD4 paralogs share high sequence and structural similarities, they exhibit distinct binding preferences. In this study, we implemented all-atom molecular dynamics simulations to investigate the interactions of the BRD3 and BRD4 ET domain with known peptide epitopes binders. Our simulations reveal that paralog-specific recognition is driven by subtle variations in loop dynamics, which encompass two divergent sites, which in turn influence the secondary structure propensities of flanking regions. These findings highlight differences in global dynamic behavior of BET-ET domains, providing mechanistic insights that might guide paralog-selective peptide-based targeting strategies.
Herrera et al. (Sun,) studied this question.